Long-term comparison between blind and ultrasound-guided corticoid injections in Morton neuroma.

OBJECTIVES: This work compares the effectiveness of blind versus ultrasound (US)-guided injections for Morton neuroma (MN) up to 3 years of follow-up. METHODS: This is an evaluator-blinded randomised trial in which 33 patients with MN were injected by an experienced orthopaedic surgeon based on anatomical landmarks (blind injection, group 1) and 38 patients were injected by an experienced musculoskeletal radiologist under US guidance (group 2). Patients were assessed using the visual analogue scale and the Manchester Foot Pain and Disability index (MFPDI). Injections consisted of 1 ml of 2% mepivacaine and 40 mg triamcinolone acetonide in each web space with MN. Up to 4 injections were allowed during the first 3 months of follow-up. Follow-up was performed by phone calls and/or scheduled consultations at 15 days, 1 month, 45 days, 2 months, 3 months, 6 months and 1, 2 and 3 years. Statistical analysis was performed using unpaired Student's t tests. RESULTS: No differences in age or clinical measures were found at presentation between group 1 (VAS, 8.5 ± 0.2; MFPDI, 40.9 ± 1.1) and group 2 (VAS, 8.4 ± 0.2; MFPDI, 39.8 ± 1.2). Improvement in VAS was superior in group 2 up to 3 years of follow-up (p < 0.05). Improvement in MFPDI was superior in group 2 from 45 days to 2 years of follow-up (p < 0.05). Satisfaction with the treatment was higher in group 2 (87%) versus group 1 (59.1%) at 3 years of follow-up. CONCLUSION: Ultrasound-guided injections lead to a greater percentage of long-term improvement than blind injections in MN. KEY POINTS: • Ultrasound-guided corticosteroid injections in Morton neuroma provide long-term pain relief in more than 75% of patients. • Ultrasound-guided injections in Morton neuroma led to greater long-term pain relief and less disability than blind injections up to 3 years of follow-up. • The presence of an ipsilateral neuroma is associated with worse long-term disability score.

Characterization of neuromas in peripheral nerves and their effects on heterotopic bone formation.

The formation of neuromas involves expansion of the cellular components of peripheral nerves. The onset of these disorganized tumors involves activation of sensory nerves and neuroinflammation. Particularly problematic in neuroma is arborization of axons leading to extreme, neuropathic pain. The most common sites for neuroma are the ends of transected nerves following injury; however, this rodent model does not reliably result in neuroma formation. In this study, we established a rodent model of neuroma in which the sciatic nerve was loosely ligated with two chromic gut sutures. This model formed neuromas reliably (∼95%), presumably through activation of the neural inflammatory cascade. Resulting neuromas had a disorganized structure and a significant number of replicating cells. Quantification of changes in perineurial and Schwann cells showed a significant increase in these populations. Immunohistochemical analysis showed the presence of ß-tubulin 3 in the rapidly expanding nerve and a decrease in neurofilament heavy chain compared to the normal nerve, suggesting the axons forming a disorganized structure. Measurement of the permeability of the blood-nerve barrier shows that it opened almost immediately and remained open as long as 10 days. Studies using an antagonist of the ß3-adrenergic receptor (L-748,337) or cromolyn showed a significant reduction in tumor size and cell expansion as determined by flow cytometry, with an improvement in the animal's gait detected using a Catwalk system. Previous studies in our laboratory have shown that heterotopic ossification is also a result of the activation of neuroinflammation. Since heterotopic ossification and neuroma often occur together in amputees, they were induced in the same limbs of the study animals. More heterotopic bone was formed in animals with neuromas as compared to those without. These data collectively suggest that perturbation of early neuroinflammation with compounds such as L-748,337 and cromolyn may reduce formation of neuromas.

Ultrasound-guided injection of steroid in multiple postamputation neuromas.

After limb amputation, neuromas may be asymptomatic when not compressed, but can cause unexplained discomfort when a prosthesis is worn. The sonographic presentation of multiple postamputation neuromas has rarely been reported. A 40-year-old female with a left, below-elbow amputation suffered from late-onset stump pain and prosthesis intolerance. Physical examination revealed a painful nodule, whereas sonographic findings disclosed three hypoechoic masses derived from the median, ulnar, and radial nerves. Marked pain reduction was reported 2 weeks after sonography-guided steroid injection. Investigation of all damaged nerves in the residual limbs is important.

Alcohol injection for Morton's neuroma: a five-year follow-up.

BACKGROUND: Although many treatment modalities are available for Morton's neuroma (MN), studies looking at the long-term effectiveness of most forms of treatment are scarce. The injection of MN with alcohol has gained popularity over the past 10 years with widespread media coverage. Many surgeons have anecdotally questioned the long-term effectiveness of this treatment. We reviewed a cohort of patients at an average 5-year follow-up to assess the medium-term results of alcohol injection. METHODS: We used the modified Johnson score and visual analogue scales to assess 45 of the original cohort of patients with an average follow-up of 61 months (range, 33-73 months). Any complications from the procedure were also noted. RESULTS: Our results indicated that by 5 years, 16 of 45 patients had undergone surgical treatment and a further 13 patients had return of symptoms. Only 29% (13/45) remained symptom free. The visual analog scale and modified Johnson scores showed statistically significant deterioration in patients' symptoms at 5 years following alcohol injection. CONCLUSION: Injection with alcohol sclerosant for MN has been marketed as a definitive management option comparable to surgical excision. Our investigation illustrated that although short-term results are encouraging, alcohol injection does not offer permanent resolution of symptoms for most patients and can be associated with considerable morbidity. Our investigation provides the only long-term data for alcohol injection treatment of MN. LEVEL OF EVIDENCE: Level II, prospective case series.

Patient's assessment of discomfort during ultrasound-guided injection of Morton's neuroma: selecting the optimal approach.

PURPOSE: Assess patient discomfort during two different methods of injection of Morton's neuroma. METHODS: Sixty-eight patients referred for ultrasound-guided injection of Morton's neuroma had punctures performed dorsal or plantar to the interdigital skin crease, with and without preliminary subcutaneous local anesthesia (LA). Patients rated discomfort during skin puncture (SP) and needle advancement (NA) using a visual analog scale. RESULTS: Average pain score was 4.4 ± 2.3 (1 SD) for the plantar approach and 2.9 ± 2.0 for the dorsal approach. This difference was statistically significant during SP (p < 0.01) and NA (p < 0.05). During the plantar approach with LA, mean pain score during SP was 4.4 (± 2.1) and 3.9 (± 2.8) during NA. This plantar approach without LA resulted in a pain score of 4.3 (± 2.6) and 3.8 (± 3.1), respectively. Mean pain scores for patients injected from the dorsal approach with LA during SP were 3.8 (± 2.7) and NA were 2.2 (± 2.0) and without LA were 2.6 (± 1.9) and 3.0 (± 2.1). There was no statistical significance in mean pain score difference during SP and NA, with and without LA for either the plantar (p > 0.05) or the dorsal (p > 0.05) approach. CONCLUSIONS: Injection of Morton's neuroma was better tolerated via a dorsal approach and use of preliminary LA did not confer any benefit.

Efficacy of corticosteroid injection versus size of plantar interdigital neuroma.

BACKGROUND: The aim of this prospective study was to assess the effectiveness of a single ultrasound-guided steroid injection in the treatment of Morton's neuromas and whether the response to injection correlates with the size of the neuroma. METHODS: Forty-three patients with clinical features of Morton's neuroma underwent ultrasound scan assessment. Once the lesion was confirmed in the relevant web space, a single corticosteroid injection was given using 40 mg of methylprednisolone along with 1% lidocaine. All scans and injections were performed by a single musculoskeletal radiologist. Patients were divided into two groups on the basis of the size of the lesion measured on the scan. Group 1 included patients with neuromas of 5 mm or less and group 2 patients had neuromas larger than 5 mm. A visual analog scale (VAS) for pain (scale 0 to 10), the American Orthopaedic Foot and Ankle Society (AOFAS) score, and the Johnson satisfaction scale were used to assess patients before injection and then at 6 weeks, 6 months, and 12 months following the injection. Thirty-nine patients had confirmed neuromas. Group 1 (lesion ≤ 5 mm) included 17 patients (mean age, 30 years) (7 males, 10 females) and group 2 (lesion >5 mm) had 22 patients (mean age, 33 years) (8 males, 14 females). RESULTS: VAS scores, AOFAS scores, and Johnson scale improved significantly in both groups at 6 weeks (p < .0001). At 6 months postinjection, this improvement remained significant only in group 1 with all scores (p < . 001). At 12 months, there was no difference between both groups and outcome scores nearly approached preinjection scores. At the final review, two patients in group 1 and four patients in group 2 had severe recurrent symptoms and therefore underwent surgical excision of the neuroma after they rejected the offer for a repeat injection (p = 0.6). CONCLUSION: A single ultrasound-guided corticosteroid injection resulted in generally short-term pain relief for symptomatic Morton's neuromas. The effectiveness of the injection appears to be more significant and long-lasting for lesions smaller than 5 mm.

Multifunctional chitin-based hollow nerve conduit for peripheral nerve regeneration and neuroma inhibition.

The recoverability for peripheral nerve lesions with a long segment defect is much challenging. Conventional methods for sciatic nerve repair excepted for autografts are bridged with nerve guidance conduit (NGC). Herein, the chitin-based NGC (ChT NGC) is firstly reported by facile dissolution, molding and regeneration process, performed excellent nerve regeneration and neuroma inhibition after deposited with anti-inflammatory polydopamine (ChT-PDA NGC). In 10 mm sciatic nerve defect rat model, the restorative effects of ChT-PDA NGC groups are similar to autografts. That is mainly ascribed to the high activity of Schwann cells and claimed by immunofluorescence staining and Western blot analysis. Interestingly, ChT-PDA NGC presents outstanding neuroma inhibition during the nerve regeneration as for the anti-inflammatory activity of PDA. This work provides a facile and novel approach to prepare hollow chitin hydrogel tube, which presents well nerve regeneration and neuroma inhibition, improving the potential high-value application of chitin in biomedical fields.

Medium-Term Results of Corticosteroid Injections for Morton's Neuroma.

BACKGROUND: The objective of this study was to evaluate the medium-term results of corticosteroid injections for Morton's neuroma. METHODS: This was a prospective follow-up study of a previous randomized controlled trial (RCT). Forty-five neuromas in 36 patients were injected with a single corticosteroid injection either with or without ultrasound guidance. As the results of the RCT showed no difference in outcomes between techniques, the data were pooled for the purpose of this study. Questionnaires were sent out and responses were collected via mail or telephone interview. Results were available in 42 out of 45 neuromas. There was a sex split of 68% female/32% male with a mean age of 62.6 years (SD, 12 years). RESULTS: At mean follow-up of 4.8 years (SD, 0.91 years), the original corticosteroid injection remained effective in 36% (n = 16) of the patients. In these cases, the visual analog scale (VAS) pain score (P < .001) and Manchester-Oxford Foot Questionnaire Index (MOxFQ Index) (P = .001) remained significantly better than preintervention scores. The remaining cases underwent either a further injection or surgery. Fifty-five percent of the 11 neuromas that received a second injection continued to be asymptomatic in the medium term. Overall, 44% (n = 20) of the initial cohort underwent surgical excision by the medium-term follow-up. The VAS score, MOxFQ Index, and satisfaction scale score across all groups were not significantly different. CONCLUSION: Corticosteroid injections for Morton's neuroma remained effective in over a third of cases for up to almost 5 years. A positive outcome at 1 year following a corticosteroid injection was reasonably predictive of a prolonged effect from the injection. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Efficacy of a Single Corticosteroid Injection for Morton's Neuroma in Adults: A Systematic Review.

BACKGROUND: Morton's neuroma is a common condition that routinely presents in podiatric practice. The aim of this study was to systematically synthesize the evidence relating to the effectiveness of a corticosteroid injection for Morton's neuroma. METHODS: Studies with a publication date of 1960 or later were eligible, and searches were performed within the Turning Research Into Practice database; the Cochrane Central Register of Controlled Trials; the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register; MEDLINE (Ovid); PubMed; Embase; Cumulative Index to Nursing and Allied Health Literature; and the gray literature. Study selection criteria included randomized and nonrandomized controlled trials where a single corticosteroid injection for Morton's neuroma pain was investigated. The primary outcome was Morton's neuroma pain as measured by any standard validated pain scale. RESULTS: Ten studies involving 695 participants were included. The quality of the studies was considered low and subject to bias. Of the included studies, five compared corticosteroid injection to usual care, one compared corticosteroid injection to local anesthetic alone, one compared ultrasound-guided to non-ultrasound-guided injections, three compared corticosteroid injections to surgery, one compared small to large neuromas, six assessed patient satisfaction, four measured adverse events, one studied return to work, and one examined failure of the corticosteroid injection to improve pain. Overall, these studies identified a moderate short- to medium-term benefit of corticosteroid injections on the primary outcome of pain and a low adverse event rate. CONCLUSIONS: A single corticosteroid injection appears to have a beneficial short- to medium-term effect on Morton's neuroma pain. It appears superior to usual care, but its superiority to local anaesthetic alone is questionable, and it is inferior to surgical excision. A very low adverse event rate was noted throughout the studies, indicating the intervention is safe when used for Morton's neuroma. However, the quality of the evidence is low, and these findings may change with further research.

Administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma-induced nerve sprouting, neuroma formation and bone cancer pain.

Pain often accompanies cancer and most current therapies for treating cancer pain have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomyosin receptor kinase A (TrkA) has become an attractive target for attenuating chronic pain. In the present report, we use a mouse model of bone cancer pain and examine whether oral administration of a selective small molecule Trk inhibitor (ARRY-470, which blocks TrkA, TrkB and TrkC kinase activity at low nm concentrations) has a significant effect on cancer-induced pain behaviors, tumor-induced remodeling of sensory nerve fibers, tumor growth and tumor-induced bone remodeling. Early/sustained (initiated day 6 post cancer cell injection), but not late/acute (initiated day 18 post cancer cell injection) administration of ARRY-470 markedly attenuated bone cancer pain and significantly blocked the ectopic sprouting of sensory nerve fibers and the formation of neuroma-like structures in the tumor bearing bone, but did not have a significant effect on tumor growth or bone remodeling. These data suggest that, like therapies that target the cancer itself, the earlier that the blockade of TrkA occurs, the more effective the control of cancer pain and the tumor-induced remodeling of sensory nerve fibers. Developing targeted therapies that relieve cancer pain without the side effects of current analgesics has the potential to significantly improve the quality of life and functional status of cancer patients.

Effectiveness of ultrasound-guided corticosteroid injection in the treatment of Morton's neuroma.

BACKGROUND: The purpose of this study was to evaluate the efficacy of corticosteroid injection and determine the duration of symptom-free period after treatment with a single ultrasound-guided injection for a painful Morton's neuroma. MATERIALS AND METHODS: From May 2002 to November 2003, 35 consecutive patients (7 males, 28 females) (mean age, 54; age range, 29 to 77 years) underwent a single ultrasound guided corticosteroid injection. Thirty-nine injections were performed as 4 patients had bilateral Morton's neuromas. The injection of 1.0 cc Celestone Chronodose (5.7 mg/ml) with 0.5 cc of 1% lidocaine was performed into the symptomatic intermetatarsal web-space. The efficacy of the injection was determined by the Johnson grading scale, and modified lower extremity functional scale. RESULTS: On the Johnson scale, 15 of 39 (38%) neuromas showed complete satisfaction 9 months after treatment and 11 of 39 (28%) were satisfied with minor reservations. A total of 26 of 39 (66%) neuromas had a positive outcome 9 months after the injection. On the functional daily activity (FDA) scale, 20 of 39 (51%) neuromas showed no difficulty and 4 of 39 (10%) indicated minor difficulties, which was considered a positive outcome 9 months after injection. Complete pain relief was achieved in 11 of 39 (28%) neuromas 9 months after treatment. Twelve of 39 (31%) neuromas did not respond to conservative treatment and required surgery. The results of treatment suggested improvement in efficacy if injection was used early. The size of the lesion measured on ultrasound showed no correlation with pain relief after injection. CONCLUSION: A single corticosteroid injection can offer short-term pain relief in the conservative management of Morton's neuroma.

Diagnosis of multiple endocrine neoplasia type 2B and management of its ocular features.

BACKGROUND: To describe ocular and vascular findings in a patient with multiple endocrine neoplasia type 2B. MATERIALS AND METHODS: Case report of a 31-year-old male who was referred for ocular assessment following diagnosis of a carotid artery dissection and multiple vascular anomalies. RESULTS: Clinical examination revealed a marfanoid habitus, myelinated corneal nerve fibers, neuromas in the perilimbal area, conjunctival hyperemia with peripheral corneal neovascularization, and posterior blepharitis. Diagnosis of multiple endocrine neoplasia type 2B was confirmed by genetic testing of the RET proto-oncogene. Genetic screening for hereditary aortic and peripheral vasculopathies failed to reveal an underlying cause for the vascular findings. We noted improvement of the ocular surface disease with topical corticosteroids and oral tetracyclines. CONCLUSIONS: Ophthalmologists play a vital role in recognizing this rare but lethal malignancy. We report on a patient with apart from characteristic ocular findings also staphylococcal hypersensitivity and widespread systemic vasculopathy.

Local Nogo-66 administration reduces neuropathic pain after sciatic nerve transection in rat.

Neuropathic pain after periphery nerve injury is frequently accompanied by the regeneration of the injured nerve fibers. We tested in this study whether local administration of Nogo-66, a well-studied axon growth inhibiting peptide in the central nerve system, could reduce the pain related behavior after sciatic nerve transection in rat. Nogo-66 peptide was purified as a GST fusion protein. Its inhibitory function was testified by neurite outgrowth assay of primary cultured neurons, and then it was given directly at the lesion site by a minipump for 2 weeks. Mechanical nociceptive withdrawal responses and heat hyperalgesia responses were assessed during a 4-week period, and autotomy was evaluated during a 6-week period. The results showed that the mechanical allodynia and heat hyperalgesia scores of the rats treated with GST-Nogo-66 were significantly higher than the controls between 7 and 14 days after sciatic nerve transection. The autotomy scores in the GST-Nogo-66 group were significantly lower than the controls from 28 days after surgery. Taken together, the results of our present study suggest that Nogo-66 may be utilized to decrease the neuropathic pain after periphery nerve injury.

Treatment of Morton's neuroma with alcohol injection under sonographic guidance: follow-up of 101 cases.

OBJECTIVE: Morton's neuroma is a common cause of forefoot pain. For this study, we assessed the efficacy of a series of sonographically guided alcohol injections into the lesion. SUBJECTS AND METHODS: One hundred one consecutive patients with Morton's neuroma were included in this prospective series. An average of 4.1 treatments per person were administered, and follow-up images were obtained at a mean of 21.1 months after the last treatment (range, 13-34 months). RESULTS: Technical success was 100%. Partial or total symptom improvement was reported by 94% of the patients, with 84% becoming totally pain-free. The median visual assessed pain score decreased from 8 before treatment to 0 after treatment (p < 0.001). Transitory increased local pain occurred in 17 cases (16.8%). There were no major complications. Thirty patients underwent sonography at 6 months after the last injection and showed a 30% decrease in the size of the neuroma. CONCLUSION: We conclude that alcohol injection of Morton's neuroma has a high success rate and is well tolerated. The results are at least comparable to surgery, but alcohol injection is associated with less morbidity and surgical management may be reserved for nonresponders.

Ultrasound-guided sciatic neuroma block for treatment of intractable stump pain.

A 61-year-old patient with severe stump pain required hospitalization and intravenous opioids for pain control. After evaluation by our anesthesia pain management service, we concluded that the patient had a neuroma at the site of sciatic nerve transection and that injection of a mixture of local anesthetic and corticosteroid at the site of the neuroma was the most appropriate management. Because the alternative methods of nerve localization (eg, motor stimulation, paresthesia) were unlikely to be successful, we felt that the most reliable way to accomplish this task was to use live ultrasound guidance. After a series of 4 ultrasound-guided blocks with bupivacaine and methylprednisolone acetate, the patient's pain was alleviated to the point at which it was managed with occasional doses of oral opioids.

Efficacy of chemical neurolysis for the treatment of interdigital nerve compression of the foot: a retrospective study.

BACKGROUND: Dilute alcohol injection has been described as a nonsurgical treatment option for interdigital nerve compression of the foot, also known as "Morton's neuroma." This study reviews the efficacy of the procedure in 49 feet at one treatment center. METHODS: In this historical cohort study, data from 42 patients who had undergone alcohol injection therapy were obtained from clinic records. A total of 49 feet were reviewed. RESULTS: Symptoms were improved or resolved in 30 (61%) of 49 feet. Nineteen feet (39%) were unimproved, with 12 of those progressing to surgical neurectomy. Feet that received five or more injections were more likely to improve (74%) than those that received fewer than five injections (39%). Three patients reported mild complications associated with dilute alcohol injection, all of which resolved spontaneously within 2 days of the injection. CONCLUSIONS: Dilute alcohol injection is a safe and effective treatment option for patients with Morton's neuroma who want to avoid a surgical procedure and any associated complications. The procedure may be more successful if the patient receives at least five injections.

Ultrasound guided steroid injection in the treatment of interdigital neuralgia.

The aim of this study was to assess the clinical effectiveness of ultrasound guided injection in the management of Morton's Metatarsalgia. Patients clinically diagnosed with interdigital Morton's neuroma were treated with ultrasound guided injection of local anaesthetic and steroid. Fifty four patients were available for follow-up, and all had detailed telephone questionnaires completed. These questionnaires included a pre and post injection symptom score, and Johnson Satisfaction score. The results indicate that 69% of patients had ultrasound diagnosis of Morton's neuroma and 31% had an ultrasound diagnosis of intermetatarsal bursa. Mean follow-up was 11.4 months. Sixty seven percent of the patients were satisfied with the results of treatment. At follow-up 63% of patients had no limitation in activity levels, and had no need to modify shoe wear. Of all patients included in the study, only three have gone on to require surgery for ongoing symptoms. Although some studies have suggested that neither injection nor imaging have a role in the treatment of Morton's neuroma, this study, however, demonstrates that ultrasound guided placement of local anaesthetic and steroid in either an intermetatarsal bursa or Morton's neuroma gives a good short and medium-term symptom relief and in the majority of cases avoids or at least delays the need for surgery.

[Surgical treatment of painful amputation neuromas with hyaluronic acid gel. Preliminary study of six patients]. / Trattamento chirurgico dei neuromi d'amputazione dolorosi con gel di acido ialuronico. Lavoro preliminare su 6 casi.

Amputation neuroma is the consequence of a traumatic event that interrupt the anatomic structure of a nerve. After the lesion, the nerve begin an plerosis attempt. This condition determines hyposensitivity on its innervation area and a painful syndrome. The pattern's resolution is possible with the neuroma's tissue exeresis and the sinking of proximal stump into closer tissue. This operation reduces or eliminates axonal nerve's flux. The hyaluronic acid (Hyaloglide 0.8-1 ml) use is based on the necessity of proximal stump preservation from mechanical and thermic stimuli that are responsible of typical neuroma's symptoms. In this study we used hyaluronic acid on six painful amputation neuroma patterns on sensitive nerves of upper and lower extremities.

Immunohistochemical profile of transforming growth factor-beta1 and basic fibroblast growth factor in sciatic nerve anastomosis following pinealectomy and exogenous melatonin administration in rats.

Collagen scar formation at the cut end of a peripheral nerve, an important problem in clinical practice for neurosurgeons, obstructs sprouting of axons into appropriate distal fascicles, and thereby limits the regeneration process. Researchers have attempted to control collagen accumulation and neuroma formation with various physical and chemical methods, but with limited functional success. Recently, it has been demonstrated that transforming growth factor (TGF)-beta and basic fibroblast growth factor (bFGF) play an important role in collagen production by fibroblasts and in Schwann cell activity. In our study, rats were divided into a control group, a melatonin-treated group, a surgical pinealectomy group, and a group treated with melatonin following pinealectomy. They then underwent a surgical sciatic nerve transection and primary suture anastomosis. At 2 months after anastomosis, the animals were sacrificed and unilateral sciatic nerve specimens, including the anastomotic region, were removed and processed for immunohistochemical study from two animals in each group. For each antibody, immunoreactivity was assessed using a semiquantitative scoring system. Strong TGF-beta1 and/or bFGF expression was observed in the epineurium of animals that underwent pinealectomy, but no or weak staining was observed in animals in the control and melatonin treatment groups. Based on these data, we suggest that both TGF-beta1 and bFGF have important roles in control of collagen accumulation and neuroma formation at the anastomotic site, and that the pineal neurohormone melatonin has a beneficial effect on nerve regeneration.